Adult-derived stem cells and their potential for use in tissue repair and molecular medicine

This report reviews three categories of precursor cells present within adults. The first category of precursor cell, the epiblast-like stem cell, has the potential of forming cells from all three embryonic germ layer lineages, e.g., ectoderm, mesoderm, and endoderm. The second category of precursor cell, the germ layer lineage stem cell, consists of three separate cells. Each of the three cells is committed to form cells limited to a specific embryonic germ layer lineage. Thus the second category consists of germ layer lineage ectodermal stem cells, germ layer lineage mesodermal stem cells, and germ layer lineage endodermal stem cells. The third category of precursor cells, progenitor cells, contains a multitude of cells. These cells are committed to form specific cell and tissue types and are the immediate precursors to the differentiated cells and tissues of the adult. The three categories of precursor cells can be readily isolated from adult tissues. They can be distinguished from each other based on their size, growth in cell culture, expressed genes, cell surface markers, and potential for differentiation. This report also discusses new findings. These findings include the karyotypic analysis of germ layer lineage stem cells; the appearance of dopaminergic neurons after implantation of naive adult pluripotent stem cells into a 6-hydroxydopamine-lesioned Parkinson's model; and the use of adult stem cells as transport mechanisms for exogenous genetic material. We conclude by discussing the potential roles of adult-derived precursor cells as building blocks for tissue repair and as delivery vehicles for molecular medicine.     

Shifting reproductive success in a shoal of Atlantic Cod, Gadus morhua L.

Individual and temporal variability in the spawning behaviour of Atlantic Cod (Gadus morhua L.) was examined by studying wild and reared individuals from the same putative population in a common spawning arena. The number of eggs fertilized per male was best explained by the number of aggressive interactions initiated by each male. A strong skew in male reproductive success and a temporal shift in male fertilization success were also observed. The latter co-occurred with an apparent similar temporal shift in the reproductive behaviour of the individual males. We hypothesize that energetic costs associated with reproduction, potentially mediated by sperm depletion in dominant individuals, may be responsible for temporal shifts in mating behaviour and reproductive success of male Atlantic Cod. We suggest that this hypothesis merits further study.     

A multigene framework for polychaete phylogenetic studies

Producing a robust phylogenetic reconstruction for Polychaeta using either morphological or molecular data sets has proven very difficult. There remain many conflicts between morphological analyses and hypotheses based on DNA data, the latter principally derived from 18S rRNA sequences. For the present study a data set covering a broad range of polychaete diversity was assembled, including 38 new sequences from 21 species. Besides available 18S rRNA data, five additional gene segments were examined: the D1 and D9-10 expansion regions of 28S rRNA, histone H3, snU2 RNA and cytochrome c oxidase subunit I. Maximum parsimony, maximum likelihood and Bayesian analyses were conducted.Annelida and Mollusca were reciprocally monophyletic in maximum likelihood analyses, but Polychaeta included a cephalopod in maximum parsimony analyses, and a patellogastropod in Bayesian analyses. When rooted on the Mollusca, optimal topologies from maximum likelihood analyses showed a recognisable basal group of taxa, including Oweniidae, Chaetopteridae and Amphinomidae. The six studied phyllodocidan families plus Orbiniidae (as the sister group of the scale-worms) formed the next most basal group. All analyses support the inclusion of Echiura, Clitellata and Siboglinidae within polychaetes. Bayesian analyses show Echiura as the sister group of Capitellidae, in agreement with previous 18S rRNA results, In contrast, Echiura formed the sister group to Trichobranchidae in maximum likelihood and maximum parsimony analyses.Supra-familial groupings consistently recovered within Polychaeta in the analyses are: (i) Terebellida without Ampharetidae; (ii) Scolecida (excepting Orbiniidae); (iii) Eunicidae, Lumbrineridae and Clitellata; and (iv) “Cirratuliformia” (including Sternaspidae) plus Sabellidae, Serpulidae and Spionidae.     

Routes of intraspecies transmission of Mycobacterium avium subsp. paratuberculosis in rabbits (Oryctolagus cuniculus): a field study

Rabbits have been increasingly linked to the persistence of paratuberculosis (Johne's disease) in domestic ruminants in the United Kingdom. The aims of this study were to determine the routes of intraspecies transmission of Mycobacterium avium subspecies paratuberculosis (MAP) in rabbits and to estimate the probability of transmission via each route, in order to gain understanding of the dynamics of MAP in this host. Rabbits were sampled from two sites where MAP had previously been isolated from the livestock and rabbit populations. No pathology was noted in any animals, but the overall prevalence of MAP in rabbits was high at both sites studied, 39.7% and 23.0%, respectively. MAP was isolated from the testes, uterus, placenta, fetuses, and milk. This is the first time that the bacterium has been isolated from any of these tissues in a nonruminant wildlife species. These results suggest that transmission may occur vertically, pseudovertically, and horizontally. Vertical, i.e., transplacental, and/or pseudo-vertical, i.e., through the ingestion of contaminated milk and/or feces, transmission occurred in 14% of offspring entering the population at 1 month of age. As infection via these routes is only possible from infected adult females, this equates to a probability of infection via this route of 0.326. Probability of infection via horizontal transmission (including interspecies transmission) occurred at up to 0.037 per month. The presence of these routes of transmission within natural rabbit populations will contribute to the maintenance of MAP infections within such populations and, therefore, the environment.     

Identification of a series of 1,3,4-oxadiazol-2-amines as potent alpha-7 agonists with efficacy in the novel object recognition model of cognition

A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.     

STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma

Constitutive activation of STAT3 is a common feature in many solid tumors including non-small cell lung carcinoma (NSCLC). While activation of STAT3 is commonly achieved by somatic mutations to JAK2 in hematologic malignancies, similar mutations are not often found in solid tumors. Previous work has instead suggested that STAT3 activation in solid tumors is more commonly induced by hyperactive growth factor receptors or autocrine cytokine signaling. The interplay between STAT3 activation and other well-characterized oncogenic "driver" mutations in NSCLC has not been fully characterized, though constitutive STAT3 activation has been proposed to play an important role in resistance to various small-molecule therapies that target these oncogenes. In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations. We further show that genetic or pharmacologic inhibition of the gp130/JAK2 signaling pathway disrupts activation of STAT3. Interestingly, treatment of NSCLC cells with the JAK1/2 inhibitor ruxolitinib has no effect on cell proliferation and viability in two-dimensional culture, but inhibits growth in soft agar and xenograft assays. These data demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations.